Induction of the Epstein-Barr virus thymidine kinase gene with concomitant nucleoside antivirals as a therapeutic strategy for Epstein-Barr virus-associated malignancies.

Abstract

Lymphoproliferative diseases (LPDs) associated with the Epstein-Barr virus (EBV) include non-Hodgkin lymphomas, which occur in the setting of immunosuppression, including that induced by human immunodeficiency virus, and posttransplant lymphoproliferative disorders. These LPDs are characterized by actively proliferating, latently infected EBV-positive B lymphocytes and often follow a rapidly progressive fatal clinical course. Pharmacologic treatment for herpesvirus infections has targeted the virus-specific enzyme, thymidine kinase (TK), with nucleoside analogs. The lack of viral TK expression in EBV-positive tumors, caused by viral latency, however, makes antiviral therapy alone ineffective as an antineoplastic therapy. Arginine butyrate selectively activates the EBV TK gene in latently infected EBV-positive tumor cells. We have developed a strategy for treatment of EBV-associated lymphomas using pharmacologic induction of the latent viral TK gene and enzyme in tumor cells using arginine butyrate, followed by treatment with ganciclovir. A phase I/II trial, using an intrapatient dose escalation of arginine butyrate combined with ganciclovir, is underway. This combination therapy has produced complete clinical responses in 5 of 10 previously refractory patients, with partial responses occurring in 2 additional patients. This virus-targeted antitumor strategy may provide a new therapeutic approach to EBV-associated neoplasms.

• Authors: D V Faller, S J Mentzer, S P Perrine
• Journal: Current opinion in oncology (Curr Opin Oncol) Vol. 13 Issue 5 Pg. 360-7 (Sep 2001) ISSN: 1040-8746 [Print] United States
• PMID: 11555713 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S., Review)

Chemical References

• Antineoplastic Agents
• Antiviral Agents
• Butyrates
• Arginine
• Thymidine Kinase
• arginine butyrate
• Ganciclovir

Topics

• Antineoplastic Agents (pharmacology, therapeutic use)
• Antiviral Agents (therapeutic use)
• Arginine (analogs & derivatives, pharmacology, therapeutic use)
• Butyrates (pharmacology, therapeutic use)
• Clinical Trials as Topic
• Combined Modality Therapy
• Enzyme Induction
• Epstein-Barr Virus Infections (complications)
• Ganciclovir (therapeutic use)
• Gene Expression Regulation, Neoplastic
• Herpesvirus 4, Human (genetics, pathogenicity)
• Humans
• Lymphoma, Non-Hodgkin (therapy, virology)
• Prognosis
• Thymidine Kinase (biosynthesis, metabolism)